tbuckley/cabot-search huggingface dataset:
KS02.5.A OVERALL SURVIVAL ASSOCIATED WITH FIRST-LINE PCV OR TEMOZOLOMIDE IN COMBINATION WITH RADIOTHERAPY IN PATIENTS WITH IDH-MUTANT, 1P/19Q CODELETED, GRADE 3 OLIGODENDROGLIOMA: ANALYSIS FROM THE POLA COHORT
Authors: S E O Kacimi, C Dehais, C Carpentier, O Chinot, C Bronnimann, E Vauleon, A Djelad, E C Moyal, M Campone, M Ducloie, G Noel, S Cuzzubbo, L Thaillandier, C Ramirez, C Colin, R Appay, E Tabouret, L Nichelli, B Mathon, A Thomas, S Tran, F Bielle, A Alentor, K Labreche, A Idbaih, D Figarella-Branger, F Ducray, M Touat
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with IDH-mutant, 1p/19q codeleted, grade 3 oligodendroglioma (Olig-3) derive benefit from the addition of alkylating agent chemotherapy to radiotherapy. However, to date, the choice between Procarbazine, Lomustine, and Vincristine (PCV) or Temozolomide (TMZ) as an optimal chemotherapy regimen for these patients remains unclear due to the lack of randomized clinical trial data comparing the two regimens. MATERIAL AND METHODS The objective was to assess the survival outcomes associated with first-line radiotherapy and PCV compared to radiotherapy and TMZ in patients with IDH-mutant, 1p/19q codeleted Olig-3 (WHO 2021). We included patients with histologically-proven IDH-mutant, 1p/19q codeleted Olig-3 from a large prospective French network cohort (POLA). The overall survival (OS) from surgery date was computed using Kaplan-Meier methods and Cox proportional hazards regression model. RESULTS A total of 306 patients with IDH-mutant, 1p/19q codeleted Olig-3 treated with radiotherapy and chemotherapy between 2008 and 2022 were included. In all, 67.6% of patients (n=207, median age at diagnosis 49.3y [IQR: 40.4-58.7]) were treated with PCV and 32.4% with TMZ (n=99, 50.3y [IQR: 43.8-61.2]) as first-line chemotherapy. Baseline characteristics were comparable between patients from both groups. The median follow-up duration was 78.4 months (IQR: 44.4-103.0). Median OS was not reached (95% CI: NR-NR) and 140 months (95% CI: 110-NR) in the PCV and TMZ groups, respectively (log rank test for OS, P=0.0023). On univariate analysis, there was a significant difference in both 5-year (PCV: 89%, 95% CI: 85-94 vs TMZ: 75%, 95% CI: 67-84; P = 0.0014) and 10-year OS (PCV: 73%, 95% CI: 62-85 vs TMZ: 60%, 95%CI: 49-73; P = 0.003) in favor of PCV. In the adjusted analysis for age, extent of resection, gender and Karnofsky performance scale (n=288), a significant OS difference between TMZ and PCV was found in the Cox proportional hazards regression model (TMZ vs. PCV HR 2.01, 95% CI: 1.16-3.50, P=0.013). CONCLUSION In the POLA cohort, among patients with IDH-mutant, 1p/19q codeleted Olig-3 receiving first-line radiotherapy combined with chemotherapy, treatment with PCV was associated with better survival compared to TMZ in both univariate and adjusted analyses. The small sample size and event rate especially in TMZ group warrants further validation. However, these results provide preliminary data on survival outcomes associated with first-line chemotherapy with PCV or TMZ in patients with IDH-mutant, 1p/19q codeleted Olig-3.
P15.14.A DIFFERENTIATE TREATMENT EFFECTS FROM DISEASE PROGRESSION IN TREATED BRAIN TUMOR: PROMISING RESULTS USING DELAYED CONTRAST MRI
Authors: P Navarria, F Pessina, L Bellu, S Politi, G Savini, E Clerici, B Marini, M Scorsetti
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Treatment effects are reported in about 30% of treated glioma and brain metastases (BMs) characterized by increasing volume of contrast enhancing regions on MRI, similarly to tumor progression. Data interpretation are often difficult. The most methodology used to distinguish this 2 conditions is perfusion MRI; treatment effects are characterized by a decreased relative cerebral blood volume (rCBV) while persistent or progressive tumors by high rCBV. Limits of perfusion MRI are represented by overlap between two conditions, low spatial resolution, and presence of susceptibility artifacts. To overcome this crucial issue, encouraging results have been obtained using delayed contrast MRI that through contrast clearance analysis (CCA) allows to calculate high resolution maps called “treatment response assessment maps” (TRAMs). We prospectively evaluated patients with doubtful framework between treatment effects (TE) and tumor progression (TP) aiming to assess the ability of CCA in differentiate this two conditions in a cohort of treated brain tumor patients. MATERIAL AND METHODS Maps (TRAMS) were calculated through contrast clearance analysis (CCA) by subtracting ceT1MRI images acquired 5 minutes after contrast injection from images acquired at least 60-105 minutes after. Diagnosis of persistent tumors or disease progression was based on presence of contrast clearance (CC) region in blue, and treatment effects on contrast accumulation (CA) region in red. Data of CCA were compared to perfusion MRI. All images were uploaded, co-registered and elaborate into the image workstation of Brainlab. Whole tumor and enhancing tumor volumes were segmented and perfusion measures in area of signal alteration. TRAMs were generated and at last the calculation of effective volume of viable tumor tissue (CC region) and treatment-induced tissue changes within each lesion (CA region) have been calculated. RESULTS From February 2021 and November 2022, 62 patient (96 delayed-contrast-MRI) with doubtful framework between TE and TP underwent CCA and perfusion-MRI. Twenty-five treated for newly diagnosed glioma, 13 for recurrence, and 37 for BMs. Significantly increased rCBV value in CC regions compared to CA was observed (p=0.01). Patients with TP showed significantly greater CC that subjects with stable disease/partial response 33% vs 78% (p=0.01). TRAMs metric were in agreement with perfusion results. Greater accuracy of TRAMs compared to perfusion-MRI in discriminate TE from TP 81% vs 69% has been observed. CONCLUSION In our experience CCA tool compared to perfusion MRI had a greater accuracy in discriminating true tumor progression from treatment induced tissue changes, and can be of improvement in patient management.
P13.12.A SUBTYPES AND SURVIVAL ANALYSIS ANALYSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH RADIOMICS FEATURES
Authors: N BARILLOT, I HERNANDEZ, E KIRASIC, C HOUILLIER, K MOKHTARI, K HOANG-XUAN, A ALENTORN
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary Central Nervous System Lymphoma (PCNSL) is a rare and heterogeneous disease with dismal prognosis. Recently, four molecular clusters with clinical relevance have been identified with different potential therapeutic targets in each group. Nevertheless, multi-omics data collection and analysis are expensive and not adapted for clinical practice. Therefore, the identification of surrogate markers to identify PCNSL subtypes from routine data is required, like using hematoxylin and eosin slides from brain biopsies. MATERIAL AND METHODS We used a cohort of 108 patients and we selected the 5000 nuclei for each patient among roughly 1,5M nuclei. Once hematoxylin and eosin slides have been digitized, tessellated, normalized and the nuclei have been segmented and filtered with the computation of a solidity score, the PyRadiomics package provides us with more than 800 features for each nuclei. Firstly, we were interested in survival analysis. In a second time, we also used these features for training classification models. We used a partial least squared Cox model, which is a classic Cox model applied to latent components constructed by using linear combinations of the original variables. RESULTS Results for our first cohort are promising (C-index of 0.87, std 0.01), with a significant increase compared to the clinical features model (C-index of 0.68, std 0.03). We are now challenging these results with three other cohorts of brain and systemic lymphoma. CONCLUSION This study paves the way for a stratification of the clinical evolution based on the machine learning analysis of digital pathology in PCNSL that could be easily translated to a broad range of diseases or other brain tumors.
P11.37.B RADIOSURGERY-ASSOCIATED NEW-ONSET FACIAL SPASM AFTER THE TREATMENT OF VESTIBULAR SCHWANNOMA IS ASSOCIATED WITH INCIDENCE OF RECURRENCE
Authors: S Wang, G Naros, A van Eck, G Horstmann, M Tatagiba
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Facial function preservation in the care of vestibular schwannoma (VS) is pre-dominantly measured in motoric function (e.g. House-Brackman (HB)). Facial spasm (FS) has been reported to be a possible side-effect in the radiosurgical treatment of VS. However, the exact incidence of FS is still unclear. MATERIAL AND METHODS This study aims to study the incidence of FS in the treatment of VS. Patient medical records of patients treated by treatment of VS between 2004 and 2020 ere analyzed retrospectively. Patient and tumor characteristics were analyzed (i.e., sex, age, tumor extension and size, intracanalicular extension). RESULTS N=104/1’998 (5%) of all patients treated by SRS presented with new-onset FS postinterventionally. FS was unrelated to tumor size. The incidence of new-onset FS was significantly higher in women (6%) compared to men (4%) (p=0.032). From all patients with FS, N=24/104 (23%) of new onset FS appeared after Re-SRS (second SRS treatment). In primary SRS therapy, facial spasm was associated with a higher recurrence rate of N=20/80 (25%) vs N=252/1"894 (13%) in nonFS patients (p=0.007). N=65/104 (62%) were permanent FS, whereas N=41/104 (39%) recovered spontaneously between 4 and 34 months, postinterventionally. The proportion (76%) of FS patients had tumors with extensive intra-canalicular extension (OHATA A-B) was higher in compared to a nonFS control group (64%) (p=0.015). CONCLUSION FS is a SRS therapy-related side effect with an overall incidence of 5%. Women were more commonly affected by new-onset SRS. Second-line SRS has the highest risk for new-onset FS. FS was associated with a higher incidence of recurrence compared to non-FS VS patients. Patients" consultation should address the relevant side effect.
P02.02.B LOSS OF ELAVL2 PROMOTES MAINTENANCE AND TUMORIGENIC COMPETENCE IN GLIOBLASTOMA
Authors: C M Argento, A Modelska, J Zasso, A Soldano, E Dassi, E Destefanis, G Ricci, M C Mione, A I Idilli, S Longhi, E F Rosatti, D Sighel, F Broso, A Quattrone
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND IDH1 wild type glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. It has been proven that it is driven by glioma stem cells (GSCs) that govern tumor growth and determine treatment resistance. GSCs transit between active and quiescent states, whose balance is likely dependent on both cell-autonomous and microenvironmental signals. MATERIAL AND METHODS transgenic cell lines were produced by retroviral infection following standard protocols, as well as zebrafish growths and orthotopic mouse brain transplants. Transgenic Drosophila lines were crossed with conventional procedures. Phenotypic evaluations, iClip protocol were conducted with standard methods as well. RESULTS in our study, we identified the gene ELAVL2, encoding the HuB protein, as commonly lost in GBM. We demonstrated that the ELAVL2 deletion occurs collaterally with the CDKN2A/B deletion, very close in the 9p21 region, but it is also present as an independent event. Rescue of HuB expression on a panel of ELAVL2-null GSCs affects their invasive ability and shifts their cell state toward differentiation, with loss of self-renewal and multipotency. A reduction in the proportion of quiescent cells determines an increased cytotoxicity of the drug temozolomide (TMZ).We validated these results in vivo, in two different animal models, showing that the tumorigenic potential of xenotransplanted ELAVL2-rescued GSCs is greatly reduced with respect to the ELAVL2-null GSCs in zebrafish and in the mice brain. We also analyzed the effects of ELAVL2 silencing, through RNAi, in a GBM genetic model in D. melanogaster, observing an increased brain volume when Rbp9, the ELAVL2 ortholog in Drosophila, is silenced. Profiling of HuB target mRNAs in GSCs highlighted genes associated with PTEN and stem cells related pathways. PTEN is upregulated in ELAVL2-rescued GSCs and mediates part of the effects of HuB, as PTEN knock-down in the same cells interferes with cell growth and TMZ-sensitivity. In our Rbp9-silenced Drosophila genetic model PTEN overexpression rescues the Rbp9 phenotype, reducing brain volume. CONCLUSION our results, both in vitro and in vivo, indicate that ELAVL2 acts as a tumor suppressor in GBM and its selective loss increases the fitness of GSCs, thus resulting in increased GBM aggressiveness. ELAVL2 promotes activation and neuronal commitment of quiescent GSCs and PTEN is one of the mediators of ELAVL2 in tumor development.
P17.09.B REIRRADIATION AS A SALVAGE THERAPY FOR LOCAL GLIOBLASTOMA RECURRENCE
Authors: A Lucas Calduch, M Macià Garau, S Villà Freixa, G Plans Ahicart, C Mesía Barroso, C Majós Torró, A Pons Escoda, N García Expósito, N Vilariño Quintela, M Mosteiro Lamas, R Velasco Fargas, M Simó Parra, R Cuadros Margarit, A Esteve Gómez, J Bruna Escuer
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND There is a lack of successful strategies to treat glioblastoma (GB) recurrences. Reirradiation is one of them, but it only can be considered in a few patients with localized relapses. This review aims to analyse the role of reirradiation in this setting and the management difficulties associated with this strategy. MATERIAL AND METHODS We have retrospectively reviewed the outcome of GB patients treated with surgery and the standard Stupp regimen, that have received stereotactic radiotherapy (RT) at the time of a local in-field relapse in our centre, during the period from 2005 to 2022. RESULTS 44 patients have been identified. The recurrence occurred at a median time of 9.7 months (m) after the end of the first RT. It was the first relapse in 89% of patients, and RT was given exclusively in 47.7% of cases. In the remaining patients, RT was combined with other treatments. The median maximum diameter of the relapse was 13.5 mm. Treatment schemes were mainly two: 35 Gy in 3.5 Gy daily fractions (52%) and 20 Gy in 5 Gy daily fractions (39%). Acute toxicity was mild, with worsening of previous neurological symptoms in only 15% of patients. After a median follow-up of 15 m, radiological responses were observed in 40% of patients, with a remarkable number of distant progressions in less than 6m (32.5%). The median time to progression was 4.8 m, being longer for patients treated at first relapse, females and with a Karnofsky index (KI) &amp;gt;70. The diameter of the relapse showed a tendency to impact in time to progression, but no differences for RT dose, RT scheme or type of strategy (exclusive RT vs combined) have been detected. The median overall survival after reirradiation was 14.9 m. Related prognostic factors were KI &amp;gt;70, size of the relapse (maximum diameter &amp;lt;25 mm) and reirradiation given at first relapse. Radiological changes after reirradiation were commonly observed (47% of patients); differentiating them from true local progression was often difficult. CONCLUSION Reirradiation is a feasible and safe therapeutic option to treat localized GB relapses, able to control the disease for a few months in selected patients, especially those with first recurrences and small lesions. Further studies must be performed to improve the radiological evaluation in these patients and to determine the optimal combination with other treatment modalities.
P01.06.B EVOLUTION OF NEUROCOGNITIVE FUNCTIONING AFTER RADIOTHERAPY IN PATIENTS WITH BRAIN METASTASES
Authors: E E van Grinsven, Y A Gmelich Meijling, F Cialdella, J J C Verhoeff, M E P Philippens, M J E van Zandvoort
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Brain metastases (BMs) occur in ten to thirty percent of the adult population. They present a heterogeneous population, with almost half already experiencing cognitive impairment prior to brain radiotherapy (RT). While RT aims to improve or stabilize the neurologic deficit(s), neurocognitive decline is often reported after treatment. To better understand cognitive performance after RT, we assessed the individual cognitive performance before, three months and at least eleven months after RT. METHODS The study population consisted of 32 adult patients with BMs that were referred for brain RT. An elaborate battery of neuropsychological tests was used to assess objective cognitive performance. Additionally, the Cognitive Failures Questionnaire (CFQ) and a semi-structured interview measured subjective cognitive performance and the EORTC QLQ-C30 and EQ-5D-3L were used to assess quality of life (QoL). The reliable change index (RCI) as formulated by Maassen et al. (2009) represented clinically significant change in cognitive performance at the follow-up time points, whereby RCI &amp;lt;-1.645 was denoted decline and RCI &amp;gt;1.645 improvement. This RCI takes into account test-retest reliability and practice effects. RESULTS Three months post-RT, 83% of the patients showed declines in at least one cognitive domain, with declines most frequent in memory (58%) and processing speed (36%). On the other hand, improvements were also found, especially for attention (92%) and fine motor coordination (46%). 50-60% of patients showed further decline in cognitive performance at task-level from three to eleven month follow-up, while 40% of patients showed further improvement. Multinomial logistic regressions indicated that a higher number of BMs was predictive of declined cognitive performance three months post-RT, specifically regarding executive functioning, processing speed and fine motor coordination. Additionally, patients without symptoms at the moment of BMs diagnosis more often showed declines in processing speed. BMs growth and age were not related to cognitive change. The change in cognitive performance was not related to either subjective cognitive performance or self-reported QoL. CONCLUSION Using a stringent RCI, we found patients who benefited from RT, but also patients who showed a clinical relevant cognitive decline three months post-RT. In most patients, this trend continued until at least eleven months after RT. Patients with multiple brain metastases may be particularly vulnerable to cognitive decline and death caused by tumour growth. However, life-extending RT also has its costs and thus requires careful consideration in shared decision-making regarding treatment options. GRANT INFORMATION The APRICOT study described in the current abstract as well as EG, were supported by funding from the Dutch Cancer Society “Koningin Wilhelmina Fonds (KWF)” (#11110).
P11.45.B LOCAL RECURRENCE IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS: A MULTICENTER COHORT STUDY
Authors: C Y M N Jansma, I Acem, J H Coert, W Taal, D J Grünhagen, C Verhoef, E Martin
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are rare and aggressive malignant soft-tissue sarcomas (STS) and compromise 5-10% of STS. About 40% of MPNST cases are associated with neurofibromatosis type 1 (NF1). High-grade MPNSTs have a high probability rate of a local recurrence (LR). Risk factors vary in current literature due to its rarity, as does the optimal treatment for LRs. Factors include the role of radiotherapy, surgical margins and NF1. This study investigated both gaps in knowledge. MATERIAL AND METHODS Surgically treated primary MPNSTs between 1988 to 2019 in the MONACO multicenter cohort were included. Multivariate Cox regression analyses were performed to identify factors associated with LR and overall survival (OS) after a LR diagnosis. Treatment of LR was evaluated. RESULTS A total of 507 patients were included in this analysis, of which 142 developed a first LR. A high-grade (HR 3.40; 95% CI, 1.32-8.70) , microscopically positive margins (R1) (HR 3.6; 95% CI, 2.16-6.00), and tumor size (HR 2.14; 95% CI, 1.04-4.42) were independent risk factors for the development of a LR. Radiotherapy (HR 0.43; 95% CI, 0.23-0.79), on the other hand, reduced the risk. Patients with a LR had significantly worse OS. Most LRs (50.7%) were treated surgically without additional therapy. Only a small amount of patients (11.3%) received additional radiotherapy. CONCLUSION This analysis provides important insights into clinicopathologic, and treatment factors associated with a LR and outcomes in MPNST patients. NF1 is not associated with an increased risk of developing a LR1 whereas other clinical factors are.
OS10.6.A GLIOBLASTOMA CELLS IMITATE NEURON’S EXCITABILITY IN ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES
Authors: T Tong, A Ozsvar, W Hou, M Capogna, A R Korshøj
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is a highly lethal cancer with a low treatment success rate due to its inter- and intra-patient molecular and physiological heterogeneity, and its complex interaction with brain tissue. Neuron-to-brain tumor-synaptic-communications (NBTSCs) are believed to contribute to glioma progression and tumor-induced epilepsy. However, the physiology of these synaptic interactions in the tumor-infiltrated human neocortex remains largely uncharacterized. In this study, we investigated the intrinsic electrical properties of cells and NBTSCs in the tumor-infiltrated human cortex. MATERIAL AND METHODS We established a unique experimental workflow that enables us to investigate glioma cells in acute and cultured human tumor-infiltrated brain slices. We utilized an adeno-associated virus-assisted gene delivery technique to selectively express fluorescence proteins in a cell-type specific manner. By performing fluorescence-guided whole-cell patch clamp recording, we characterized the electrophysiological properties of glioma cells and neurons under the tumor microenvironment. RESULTS We observed that glioma cells from tumor-infiltrated human brain samples display relatively depolarized -32.59 + 3.16 mV resting membrane potential and high input resistance of 1.73 + 0.43 GΩ, with 44.44% of glioma cells exhibit spikelets or distorted-action potentials upon current injection. Consistent with previous studies, some glioma cells (11.8%) from both acute and cultured human brain slices exhibit spontaneous excitatory postsynaptic currents (sEPSC). In addition, the tumor-infiltrated microenvironment significantly influences the proximal neurons’ physiology and the neuronal microcircuitry. Neurons within the tumor region show abnormal intrinsic electrical properties, depolarized resting membrane potential (-37.66 + 4.32 mV), and a significant reduction in spontaneous synaptic input frequency. CONCLUSION Collectively, we consolidate the existence of NBTSCs in human cancer patients and unprecedentedly reveal that glioma cells exhibit neuron-like excitability, which is contrary to the common understanding that they are considered as non-excitable. Under the tumor microenvironment, neurons display hyperexcitability. Our newly established organotypic human brain slice culture platform provides potential grounds for exploring further the biological characteristics of gliomas. SUPPORT/DISCLOSURE This study is supported by grants to AK (DCCC Consortium grant number R295-A16770 funded by the Danish Comprehensive Cancer Center); to MC (Lundbeck-NIH grant number R325-2019 funded by the Lundbeck Foundation, DFF-1 project 37741 funded by the Independent Research Fund Denmark).